{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T19:10:10Z","timestamp":1780341010383,"version":"3.54.1"},"reference-count":44,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T00:00:00Z","timestamp":1538611200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81772360"],"award-info":[{"award-number":["81772360"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81401785"],"award-info":[{"award-number":["81401785"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LY17H060004"],"award-info":[{"award-number":["LY17H060004"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["Y17H060027"],"award-info":[{"award-number":["Y17H060027"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Postmenopausal osteoporosis is initiated by estrogen withdrawal and is characterized mainly by over\u2010activated osteoclastic bone resorption. Targeting TNF receptor\u2010associated factor 6 (TRAF6) or its downstream signaling pathways to modulate osteoclast formation and function is an appealing strategy for osteoclast\u2010related disorders. In the present study, we determined the effect of tomatidine, a steroidal alkaloid derived from Solanaceae, on the formation and function of receptor activator of NF\u2010\u03baB (RANK) ligand\u2010induced osteoclasts and the underlying mechanism. Tomatidine inhibited osteoclast formation in a dose\u2010dependent manner and decreased the expression of osteoclast marker genes. Actin ring formation and osteoclastic bone resorption were attenuated in the presence of tomatidine\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Eight weeks after ovariectomy, tomatidine prevented estrogen deficiency\u2010induced bone loss and restored the mechanical properties of the femur. At the molecular level, tomatidine abrogated phosphorylation of c\u2010Jun N\u2010terminal kinase (JNK)\/p38, NF\u2010\u03baB, and protein kinase B (Akt) pathway proteins by suppressing RANK expression, inhibiting the binding of TRAF6 to RANK, and downregulating the osteoclastogenesis marker\u2010related protein expression. In summary, these data demonstrated that tomatidine attenuated osteoclast formation and function by modulating multiple TRAF6\u2010mediated pathways. Therefore, tomatidine could be a novel candidate for the treatment of osteoclast\u2010related disorders, including osteoporosis.\u2014Hu, B., Sun, X., Yang, Y., Ying, Z., Meng, J., Zhou, C., Jiang, G., Li, S., Wu, F., Zhao, X., Zhu, H., Wu, H., Cai, X., Shi, Z., Yan, S. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency\u2010induced bone mass loss by modulating TRAF6\u2010mediated signaling. FASEB J. 33,2574\u20132586 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201800920r","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T14:51:39Z","timestamp":1538664699000},"page":"2574-2586","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency\u2010induced bone mass loss by modulating TRAF6\u2010mediated signaling"],"prefix":"10.1096","volume":"33","author":[{"given":"Bin","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewu","family":"Sun","sequence":"additional","affiliation":[{"name":"Orthopedic Research Institute Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yute","family":"Yang","sequence":"additional","affiliation":[{"name":"Orthopedic Research Institute Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahong","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhe","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengfeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Huzhou Central Hospital Zhejiang University Huzhou Hospital Huzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanxiao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haobo","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunzi","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongli","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigui","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Second Affiliated Hospital Zhejiang University Hangzhou China"},{"name":"Department of Orthopaedics Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2062"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.5435\/00124635-201006000-00009","article-title":"The orthopaedic implications of diphosphonate therapy","volume":"18","author":"Weaver M. J.","year":"2010","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1D353"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2007.06.010"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2008.02.017"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1576"},{"key":"e_1_2_8_8_1","first-page":"559","article-title":"Role of angiogenesis on bone formation","volume":"27","author":"Portal-Nunez S.","year":"2012","journal-title":"Histol. Histopathol."},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.02.020"},{"key":"e_1_2_8_10_1","first-page":"129","article-title":"Generating murine osteoclasts from bone marrow","volume":"80","author":"Takahashi N.","year":"2003","journal-title":"Methods Mol. Med."},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2710"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf402654e"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2008.05.049"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.556241"},{"key":"e_1_2_8_16_1","first-page":"52","article-title":"Sem analysis zirconia-ceramic adhesion interface","volume":"8","author":"Cardelli P.","year":"2016","journal-title":"Oral Implantal. (Rome)"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24921"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2851"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2015.02.017"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3031"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0800642105"},{"key":"e_1_2_8_22_1","first-page":"284071","article-title":"Total phenolic, flavonoid, tomatine, and tomatidine contents and antioxidant and antimicrobial activities of extracts of tomato plant","volume":"2015","author":"Silva-Beltr\u00e1n N. P.","year":"2015","journal-title":"Int. J. Anal. Chem."},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200838192"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00369-6"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1443.016"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.12.1741"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2013.1258"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22640"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050645"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.242"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802525200"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/35085597"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.4.992-1000.2002"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.051557"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2010.01.383"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600564"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051150"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1402.071"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-09-3662"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4773"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-16-0591"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317215"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-014-1708-8"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2428"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.K.01181"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201800920R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201800920R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201800920R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T01:19:06Z","timestamp":1761700746000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201800920R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,4]]},"references-count":44,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1096\/fj.201800920R"],"URL":"https:\/\/doi.org\/10.1096\/fj.201800920r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,4]]},"assertion":[{"value":"2018-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}